The critical role of dendritic cells (DC) in the initiation of simian immunodeficiency virus (SIV) infection has recently been demonstrated in a macaque model. After vaginal exposure to SIV, DC in the lamina propria of the cervicovaginal mucosa were among the first cells in which SIV DNA was detected. Later, infected cells were observed in the subcapsular and paracortical regions of draining lymph nodes, suggesting that DC migrated from the mucosal tissue to regions of the lymph node, where HIV replication occurs throughout the course of disease in humans. Recently, chemokine receptors have been identified as necessary co-receptors for HIV entry; M-tropic viruses use CCR5, T-tropic viruses use CXCR4, and dual-tropic viruses use either CCR5, CXCR4, CCR2B or CCR3, respectively. The natural ligands for these receptors, RANTES, MIP-1alpha and MIP-1beta for CCR5 and SDF-1 for CXCR4, block infection of a CD4-positive target cell with M-tropic or T-tropic virus isolates, respectively. We have demonstrated that DC are infectable in vitro by both M-tropic and T-tropic strains of HIV. We have analyzed DC (produced in vitro by cytokine treatment of monocytes) for calcium flux, chemotaxis, mRNA, entry of HIV and flow cytometry, and have identifed multiple chemokine receptors on monocyte-derived DC (MDDC). In particular, we have identified a novel SDF-1 binding, non-CXCR4 receptor primarily used by T-tropic isolates that may, in addition to CCR5, be used by M-tropic isolates. We also detected CCR3 on MDDC that could be used by certain dual-tropic HIV isolates for infection. Since DC are also likely to be the first cell type infected after mucosal exposure in humans, study of DC infection with HIV and their expression and usage of HIV co-receptors will likely contribute to our understanding of the early events of HIV infection.